Understanding a Mysterious Leukemia

The researchers have linked a mutation causing Down syndrome-associated leukemias to specific developmental abnormalities in cells that produce platelets, megakaryocytes.

Red Blood Cells

Research at the University of Virginia School of Medicine has shed
light on a mysterious form of leukemia that can appear and then
disappear in children with Down syndrome. The findings may have
important implications for other forms of leukemia and other diseases,
possibly leading to new treatments, and could one day help people with
problems related to platelet deficiencies as well.

The researchers have linked a mutation causing Down
syndrome-associated leukemias to specific developmental abnormalities
in cells that produce platelets, megakaryocytes. Essentially, this
mutation is interfering with an enzyme, Calpain 2, that acts as an
initial trigger for a chain of reactions that determines size and shape
of megakaryocytes. This interference causes the normal process of
cellular enlargement and platelet production to get hung up. "It's like
there's a long pipeline and there's a clog," explained Adam N.
Goldfarb, MD, of the Department of
Pathology. "We think it's this pipeline that's getting clogged in
this disease and other diseases."

Leukemia cells with the mutation display a critical deficiency of
Calpain 2, and the enzyme's absence leaves them stuck in an early stage
of development, contributing to the development of Down
syndrome-associated leukemias, Goldfarb said. And that could be the
case in other forms of leukemia as well. "These leukemias in Down
syndrome aren't that common, but this finding has implications for
other leukemias in that it lets us understand basic growth and
development patterns," Goldfarb said.

Restoring Calpain 2 expression in affected cells, the researchers
found, fixed the problem and allowed the normal megakaryocyte
developmental process to resume. As such, the researchers hypothesize
that calpain deficiency could be a key defect in Down
syndrome-associated leukemias, opening up a new target for developing
more effective treatments. And, eventually, it could lead to ways for
doctors to mimic the natural process that allows a subset of Down
syndrome-associated leukemias to disappear spontaneously.

The new research is also notable for the understanding it provides
about the development and growth of megakaryocytes, the large cells
that produce platelets. Megakaryocytes recover slowly after
chemotherapy, and they're easily destroyed, so it's important to
understand how they develop and find ways to control their replication
and growth.

Megakaryocytes differ in size in neonatal infants versus older
individuals, and they behave differently as well. By understanding why,
scientists may one day be able to toggle them between the forms seen in
neonates - when they're smaller but proliferate more quickly - and in
adults, when they're more effective at platelet production. That could
prove invaluable in developing new treatments for low platelet
counts.

The findings have been published online by the journal Developmental
Cell. The article was authored by Kamaleldin E. Elagib, Jeremy D.
Rubinstein, Lorrie L. Delehanty and Valerie S. Ngoh, all of UVA; Peter
A. Greer of Queen's University in Ontario; Shuran Li and Jae K. Lee, of
UVA; Zhe Li and Stuart H. Orkin, of Harvard; and Ivailo S. Mihaylov and
Goldfarb, of UVA.

Goldfarb made particular mention of the contributions of Elagib, the
first author on the paper, saying he "gets a huge amount of credit for
persistence" in pursuing the research.